Morphine is an analgesic indispensable for an improvement in quality of life (QOL) of a patient with cancer pain. However, morphine has problems of, for example, having low bioavailability and causing various side effects, such as formation of analgesic resistance and physical or psychological dependence due to continued use, nausea and vomiting, constipation, sleepiness, and respiratory depression. Therefore, the advent of an ideal analgesic serving as a substitute for morphine has long been strongly demanded. In search of more excellent analgesics, investigations on synthetic analgesics were started with chemical modification of a morphine molecule in the 1920s, and synthesis and pharmacological activity evaluation of a large number of compounds are still performed today. However, there are few examples of development of an effective opioid analgesic substance serving as a substitute for a morphine skeleton. Meanwhile, investigations on expression of an analgesic action of morphine have also been greatly advanced in recent years, and efforts to elucidate a molecular mechanism of analgesia have been made on the basis of, for example, classification of opioid receptors (δ-, μ-, and κ-receptors) and determination of amino acid sequences thereof. However, there are complicated interactions among those three kinds of receptors, and a logical methodology for separating an analgesic property from side effects, such as a narcotic property, has not yet been established.
The present inventor and colleagues found that an alkaloid contained in a rubiaceous plant Mitragyna speciosa, which had been used as a substitute for morphine in Thailand and Malaysia, had a potent analgesic action, and then achieved isolation and efficient asymmetric total synthesis of 7-hydroxymitragynine (sometimes referred to as 7-hydroxymitragynine), an indole alkaloid that was a trace ingredient considered to be a main active principle of the alkaloid (Non Patent Literature 1). In addition, the present inventor and colleagues reported that 7-hydroxymitragynine inhibited contraction induced by electrical stimulation in guinea pig small intestine via opioid receptors (Non Patent Literature 1), and exhibited a remarkable antinociceptive action by subcutaneous administration or oral administration in a tail-flick test or a hot-plate test using mice (Non Patent Literature 2). Further, the present inventor and colleagues synthesized derivatives of 7-hydroxymitragynine and mitragynine, and reported derivative compounds exhibiting more potent analgesic actions than that of morphine and having reduced side effects (Patent Literatures 1 to 3 and Non Patent Literature 3).